The induction of transplantation unresponsiveness remains an elusive goal. Clinical applications of organ transplantation have only been possible due to the chronic use of a variety of immunosuppressive agents, which not only incompletely control allograft rejection, but also confer significant patient morbidity. This application proposes to test the hypothesis that a combined regimen of 3M KCl-extracted histocompatibility antigen (HAg), which stimulates specific T-cell suppressor functions, and a brief course of cyclosporine (CsA), a cyclic endecapeptide of novel structure which depresses T-lymphocyte helper functions, induces long-term, donor-specific allograft survival. Intravenous injection of 5 mg HAg either on day -1 (or +1) combined with 10 mg/kg po CsA on three days (-1, 0, +1) prolongs rat renal allografts transplanted across an RT-1 barrier on day 0 from 7.9 to 26.8 days. When HAg is combined with 9 doses of CsA (days -1, 0, +1, 7, 8, 9; 14, 15, 16), 50% of hosts were permanently unresponsive not only to renal allografts, but also to challenge donor-type, but not third-party, skin grafts applied at 80 days. Prolonged survival was transferred to normal syngeneic hosts with purified OX8+ cells. The proposed studies will translate the rat model to more stringent models of mouse H-2 incompatibility and outbred mongrel dogs. In addition, immunologic aspects of suppressor cell function in the rat model will be dissected in order to discover variables that optimize the induction of unresponsiveness, including purification, amplification and characterization of the rat suppressor cell (and its mouse analogue if such can be generated), as well as identifying the class nature of histocompatibility antigens inducing the phenomenon. If the experiments identify a regimen capable of inducing consistently prolonged survival in these stringent models, it will provide the foundation for immediate preclinical tests using inbred beagle dogs, and subhuman primates. Because this conditioning regimen utilizes a brief time frame consistent with the strictures of human cadaveric donor organ transplants, it proffers the opportunity to actively induce unresponsiveness in patients, thereby mitigating the need for chronic immunosuppression.